The overall number of people living with HIV-1 continues to increase worldwide. With no prospect for an effective vaccine, treating infected individuals and preventing HIV transmission from infected to uninfected individuals becomes increasingly important. Commensal bacteria that can impact systemic immunity are often involved as the first defense against viral infections. Given this knowledge, we were the first to identify a group of oligosaccharide molecules (termed CC5Ap) associated with the oral commensal bacterium Streptococcus cristatus CC5A, and found that it enhanced the expression of A3G/F and MX2, and inhibited HIV-1 replication in target cells, such as monocyte-derived dendritic cells (MD-DC). We hypothesize that CC5Ap may serve as a potential agent to prevent/treat HIV/AIDS based on its actions toward increasing the levels of A3G/F and MX2. In this application, we propose to test this hypothesis by the following three specific aims: (1) Lead compound screening and structural activity relationship (SAR) study of the lead compound for potential novel anti-HIV drug development. (2) Explore the mechanism of the lead compound in inhibiting HIV-1 replication. (3) Determine the antiviral potency and cytotoxicity of the lead compound using human cervical explants. This study will provide vital information regarding the potential of the lead compound to be a candidate for developing an anti-HIV- 1/AIDS drug, which synergistically targets both early and late stages of HIV-1 replication. As there is no clinically approved anti-HIV-1 drug based on boosting host innate immunity, this work will facilitate the development of a new class of HIV-1 antivirals.